PROJECT SUMMARY (Overall) Major depressive disorder (MDD) and anxiety disorders are major public health problems characterized by blunted approach-related behaviors and increased avoidance, which predict worse disease trajectories, increased suicide risk, and poor treatment response. Despite this compelling evidence, little is known about the neurobiological mechanisms underlying abnormal approach-avoidance behavior in these disorders, which has hampered treatment development. To address this unmet need, we propose an integrated research program through a unified Conte Center that will investigate the role of cortico-striatal-midbrain and nociceptin circuitry in approach-avoidance behaviors. The goals will be to identify novel treatment targets and markers that map disease course. These goals will be achieved by bringing together a highly interdisciplinary team with complementary expertise and an established record of successful collaboration. The team will tackle pivotal questions through a highly coordinated approach that will entail numerous conceptual and technological innovations. Guided by a large amount of preliminary data, the proposed approach spans different species (mice, non-human primates, humans), approaches (non-invasive neuroimaging, intracortical recordings and deep brain stimulation in humans; optogenetics, chemogenetics techniques, and CRISPR-cas9 knockdown in non-human animals), and units of analyses (genes, molecules, cells, circuits, physiology, behavior, self-report). Critically, to increase translational impact, functionally identical tasks will be used and identical molecular targets will be probed across three species. The Computational Modeling Core will test whether specific states (e.g., MDD, anxiety, stress-induced depressive phenotypes) or pharmacological manipulations (e.g., nociceptin receptor antagonists) have similar effects on model parameters across species, which is expected to improve the likelihood of successful translation. The unifying hypotheses are that: (1) MDD, anxiety disorders are characterized by negative biases in approach/avoidance behaviors; (2) Negative biases in approach/avoidance behaviors are linked to dysfunction in cortico-striatal-midbrain circuitry and nociceptin system upregulation; and (3) nociceptin receptor antagonists and modulation of cortico-striatal-midbrain circuitry will normalize approach/avoidance behaviors. These innovative hypotheses will be pursued through four closely intertwined Projects supported by an Administrative Core and a Computational Modeling Core. This unified research program will make unique contributions towards three NIMH Strategic Objectives: (1) A better understanding of the pathophysiology of mental illness (NIMH Strategic Objective 1.1); (2) Identification of novel treatment targets (Strategic Objective 3.1); and (3) Identification of markers that map disease course (Strategic Objective 2.2). Thus, the significance and impact of the knowledge generated by the Center will be substantial, as we aim to transform our understanding of the pathophysiology of two disorders that affect >35% of the US population, which is a necessary step towards more effective treatments.